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PubMed1999

Identification of optimal conditions for lung graft storage with Euro-Collins solution by use of a rat orthotopic lung transplant model.

BACKGROUND: Lung preservation disrupts normal vascular homeostasis, resulting in increased permeability, vasoconstriction, and endothelial cell adhesion for neutrophils. We hypothesized that a storage strategy that best preserves post-lung transplantation (LTX) vascular homeostasis might be organ and species specific. Because of the potential utility of a rat LTX model for developing improved lung preservation strategies, we have attempted to identify the optimal physical conditions for rat lung graft storage. METHODS AND RESULTS: Conditions that were tested included harvest inflation pressure (0, 10, or 20 mm Hg), inflation gas composition (100% N(2), room air, or 100% O(2)), and storage temperature (4 degrees, 10 degrees, or 15 degrees C). Modified Euro-Collins solution served as the base preservation solution for all experiments, with a preservation duration of 4 to 6 hours. Arterial oxygenation (PaO(2), mm Hg), pulmonary vascular resistance (mm Hg/mL per minute), recipient survival (%), and graft neutrophil infiltration (DeltaAbs(460 nm)/min) were measured 30 minutes after transplantation of the left lung and exclusion of the right lung from the circulation. All tested conditions significantly affect post-LTX vascular homeostasis. Inflation at 10 mm Hg pressure preserved lungs significantly better than did other pressures. There was a tendency for room air to improve all measured variables compared with 100% N(2) or 100% O(2) and a significant improvement in recipient survival with room air storage. Of the 3 storage temperatures investigated, 10 degrees C storage provided the best preservation in terms of PaO(2), graft neutrophil infiltration, and survival. CONCLUSIONS: We conclude that storage at 10 degrees C, 10 mm Hg inflation pressure, with room air establishes optimal lung storage conditions with Euro-Collins solution in this rat LTX model. These data suggest that these conditions should be used to evaluate new and potentially improved preservation strategies.

Animals↗
PubMed2005

Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization.

BACKGROUND: Bronchopulmonary dysplasia (BPD) and pulmonary emphysema, both significant global health problems, are characterized by a loss of alveoli. Vascular endothelial growth factor (VEGF) is a trophic factor required for endothelial cell survival and is abundantly expressed in the lung. METHODS AND RESULTS: We report that VEGF blockade decreases lung VEGF and VEGF receptor 2 (VEGFR-2) expression in newborn rats and impairs alveolar development, leading to alveolar simplification and loss of lung capillaries, mimicking BPD. In hyperoxia-induced BPD in newborn rats, air space enlargement and loss of lung capillaries are associated with decreased lung VEGF and VEGFR-2 expression. Postnatal intratracheal adenovirus-mediated VEGF gene therapy improves survival, promotes lung capillary formation, and preserves alveolar development in this model of irreversible lung injury. Combined VEGF and angiopoietin-1 gene transfer matures the new vasculature, reducing the vascular leakage seen in VEGF-induced capillaries. CONCLUSIONS: These findings underscore the importance of the vasculature in what is traditionally thought of as an airway disease and open new therapeutic avenues for lung diseases characterized by irreversible loss of alveoli through the modulation of angiogenic growth factors.

Adenoviridae↗
PubMed1999

Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation.

Reperfusion lung injury is an important cause of morbidity and mortality after orthotopic lung transplantation. The purpose of this study was to investigate the function of the alveolar epithelium in the setting of reperfusion lung injury. Simultaneous samples of pulmonary edema fluid and plasma were collected from eight patients with severe post-transplantation reperfusion edema. The edema fluid to plasma protein ratio was measured, an indicator of alveolar-capillary barrier permeability. The initial edema fluid to plasma protein ratio was > 0.75 in six of eight patients, confirming the presence of increased permeability of the alveolar-capillary barrier. Graft ischemic time was positively correlated with the degree of permeability (r = 0.77, p < 0.05). In four of six patients with serial samples, there was a high rate of alveolar fluid clearance (19 +/- 9%/h, mean +/- SD). Alveolar fluid clearance was calculated from serial samples in six patients. Intact alveolar fluid clearance correlated with less histologic injury, rapid resolution of hypoxemia, and more rapid resolution of radiographic infiltrates. The two patients with no net alveolar fluid clearance had persistent hypoxemia and more severe histologic injury. This study provides the first direct evidence that increased permeability to protein is the usual cause of reperfusion edema after lung transplantation, with longer ischemic times associated with greater permeability to protein in the transplanted lung. The high rates of alveolar fluid clearance indicate that the fluid transport capacity of the alveolar epithelium may be well preserved in the allograft despite reperfusion lung injury. The ability to reabsorb fluid from the alveolar space was a marker of less severe reperfusion injury, whereas the degree of alveolar-capillary barrier permeability to protein was not. Measurement of alveolar fluid clearance may be useful to assess the severity of reperfusion lung injury and to predict outcome when pulmonary edema develops after lung transplantation.

Adult↗
PubMed1999

Cardiopulmonary exercise testing before and after lung and heart-lung transplantation.

Heart-lung (HLT) and lung transplantation (LT) have been shown to be effective procedures for patients with end-stage cardiopulmonary disorders. As yet, few data exist on the exercise performance of patients before and after thoracic transplantation except with regard to 6-min walk tests. In this article we report cardiopulmonary exercise test results of lung and heart-lung transplant recipients in comparison with their pretransplant values. We studied 103 consecutive recipients of single-lung (n = 46), bilateral lung (n = 32), and heart-lung (n = 25) transplants. Cardiopulmonary exercise testing with a cycle ergometer was performed before and shortly after surgery. Before transplantation, all patients showed severe exercise intolerance and markedly impaired parameters reflecting cardiopulmonary function (e.g., work capacity: 20 +/- 11% predicted; oxygen uptake: 34 +/- 12% predicted; oxygen pulse: 50 +/- 18% predicted; functional dead space ventilation: 57 +/- 10% of minute ventilation; alveolar-arterial oxygen difference during exercise: 79 +/- 15 mm Hg). At 55 +/- 9 d after transplantation, transplant recipients reached maximum oxygen uptakes in the range of 22 to 71% of predicted values; the peak oxygen uptake was increased after transplantation (13.1 +/- 3.4 ml/min/kg versus 10.4 +/- 3.8 ml/min/kg; p < 0.001). Work capacity, oxygen pulse, tidal volume, and peak minute ventilation did not differ in patients following single- or double-lung tranplantation or HLT. Ventilatory factors did not appear to limit exercise capacity in any group. Despite the persistent limitations in aerobic capacity and work rate seen in many of the recipients, cardiopulmonary performance is reasonably well restored shortly after LT and HLT.

Adult↗
PubMed1983

The effects of intravenous infusion of saline on lung density, lung volumes, nitrogen washout, computed tomographic scans, and chest radiographs in humans.

In this study we examined the effect of a 15% increase in extracellular fluid volume on lung density, lung volumes, nitrogen washout, chest radiographs and computerized tomographic (CT) scans of the thorax in 5 volunteers. The objective of the study was to determine the sensitivity of these techniques in detecting small changes in lung water. Lung density was measured by a gamma ray Compton scatter technique and with an Ohio nuclear delta 2020 CT scanner. We measured or derived functional residual capacity, residual volume (RV), vital capacity (VC), and total lung capacity by helium dilution. Single-breath nitrogen washout was used to measure closing volume and the slope of phase III nitrogen washout (delta N2). Chest radiographs were taken in the posteroanterior and lateral projections. With the CT scanner we obtained slices 1 cm thick through the bases of the lungs and at 6 and 12 cm up from the bases. All these measurements were made before and 20 to 90 min after the intravenous infusion of 30 ml/kg body weight of warm saline over a period of 20 min. The most striking findings were a 24% increase in delta N2, a 14% increase in RV, and a 4.5% decrease in VC. Chest radiographs and the CT scans showed an increase in the size of the azygos veins. There was no change in Compton scatter density or the CT numbers. These results suggest that (1) tests of small airway function, such as RV and delta N2, are more sensitive than radiographic techniques to small increases in lung water, (2) there is some protection of the lung to increases in extracellular fluid volume.

Adult↗
PubMed2004

Pressure-volume curve does not predict steady-state lung volume in canine lavage lung injury.

To better understand strategies for recruiting and maintaining lung volume in acute lung injury, we examined relationships between steady-state lung volume and cumulative cyclic recruitment/derecruitment volume history and the quasi-static pressure-volume curve, in an animal saline lavage lung injury model. Small-volume tidal pressure-volume loops performed after inflation from functional residual capacity demonstrated incremental, cyclic recruitment only if the peak pressure achieved exceeded the pressure at which the compliance increased (Pflex) on the pressure-volume curve, whereas loops performed after deflation from total lung capacity remained close to the envelope deflation curve. Recruitment continued to occur up to and beyond a peak inspiratory airway pressure of 40 cm H(2)O, as demonstrated by both the tidal loops and by computed tomography-derived lung volume data. Tidal-specific compliance was relatively constant across positive end-expiratory pressure levels after inflation from functional residual capacity, but peaked at moderate positive end-expiratory pressure after deflation from total lung capacity, further demonstrating the effects of volume history and providing experimental validation of the recruitment models of Hickling (AJRCCM 2001;163:69-78). These results support the interpretation of Pflex as pressure threshold for recruitment, but otherwise do not suggest a role for the pressure-volume curve in predicting steady-state lung volume.

Airway Resistance↗
PubMed2005

Proliferative stimulus of lung fibroblasts on lung cancer cells is impaired by the receptor for advanced glycation end-products.

The receptor for advanced glycation end-products (RAGE) is highly expressed in lung tissue, especially at the site of the alveolar epithelium, but its expression is reduced in lung carcinomas. Because epithelial-mesenchymal interactions are suggested to contribute to cancer progression, we investigated the RAGE-dependent impact of fibroblasts on tumor cell growth. Cocultivation of human lung cancer cells (H358) with lung fibroblasts (WI-38) improved their proliferation in monolayer and spheroid culture models, the number of H358 cells in the S/G2 cell cycle phase increased, and there was less spontaneous cell death. Overexpression of full-length human RAGE reduced the proliferative stimulus of fibroblasts as seen in monolayers (cell number, cell cycle), spheroid cultures (spheroid size), and in a colony-forming assay compared with mock-transfected cells. Comparable results were observed by culturing H358 cells with and without RAGE overexpression in the presence of conditioned medium taken from WI-38 cells, or in response to selected growth factors, such as basic fibroblast growth factor. Moreover, we clearly showed that the fibroblast-induced proliferation correlates with activation of the p42/44 mitogen-activated protein kinase, but not with Akt kinase activation. On the basis of lung cancer as an age-related disease, we additionally proved the impact of senescent WI-38 fibroblasts. Here, we show that senescent fibroblasts improve H358 cell proliferation to the same extent as do presenescent fibroblasts. From our data, we conclude that re-expression of RAGE in lung cancer cells impairs the proliferative stimulus mediated by fibroblasts. Therefore, lung cancer progression may be enhanced by the RAGE downregulation in human lung carcinomas.

Animals↗
PubMed2006

Early manifestations of NNK-induced lung cancer: role of lung immunity in tumor susceptibility.

A strong correlation exists between smoking and lung cancer; however, susceptibility to lung cancer among smokers is not uniform. Similarly, mice show differential susceptibility to the tobacco carcinogen nitrosamine 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which produces lung tumors in A/J but not in C3H mice. Host immunity may play a role in the susceptibility to cancer, and cigarette smoke/nicotine suppresses the immune system through activation of nicotinic acetylcholine receptors (nAChRs). Mammalian lungs express alpha7-nAChRs, and NNK is a high-affinity agonist for alpha7-nAChRs. To examine whether NNK differentially modulates lung immunity in susceptible and resistant mouse strains, A/J and C3H mice were treated with NNK and/or immunized with sheep red blood cells. Lung tissues and RNA of treated and untreated animals were analyzed by immunohistochemistry and RT-PCR for alpha7-nAChR and COX-2 expression. Spleen- and the lung-associated lymph node cells from control and immunized animals were assessed for immunologic responses, including anti-sheep red blood cell antibody plaque-forming cells, concanavalin A-induced T-cell proliferation, and the anti-CD3/CD28 antibody-induced rise in intracellular calcium. NNK strongly suppressed these responses in A/J but not in C3H mice. Similar NNK-induced immunologic changes were seen in another pair of carcinogen-sensitive (NGP) and relatively carcinogen-resistant (B10.A) mouse strains. Moreover, NNK stimulates a significantly higher expression of COX-2 and alpha7-nAChRs in A/J than in C3H lungs. These results suggest that the susceptibility to chemical carcinogenesis among various mouse strains might be influenced by their immunologic response to the carcinogen.

ADP-ribosyl Cyclase 1↗
PubMed2003

Exhaled nitric oxide after lung transplantation: impact of the native lung.

It has already been demonstrated that exhaled nitric oxide (eNO) is increased in lung transplant patients with chronic rejection, although it is not known whether the diseased native lung after single lung transplantation (SLTx) contributes to the increased eNO values. This study aimed to compare the eNO values in stable lung transplant patients (SLTx versus sequential (S)SLTx and heart (H)LTx) and in patients with established chronic rejection. Altogether, 42 LTx patients (25 females, 13 SLTx, 18 SSLTx, 11 HLTx), with a mean follow-up of 1149 days and a mean age of 44.6 yrs at transplantation, were included. Twenty-six patients had no signs of chronic rejection (five SLTx and 21 SSLTx/HLTx). There was no difference in their eNO values (10.2 in SLTx versus 12.2 (parts per billion) ppb in SSLTx/HLTx). Sixteen patients (eight SLTx and eight SSLTx/HLTx) had a chronic rejection (eight bronchiolitis obliterans syndrome (BOS) potential stage, four BOS stage 1, three BOS stage 2 and one BOS stage 3). Their eNOs were 18.1 (SLTx) and 17.0 (SSLTx/HLTx) ppb, respectively, which were significantly different to the stable LTx patients and showed a trend towards significance for SSLTx/HLTx. There was no significant difference in eNO between the patients with chronic rejection who underwent SLTx and those who underwent SSLTx/HLTx. The diseased native lung after single lung transplantation probably does not contribute much to the exhaled nitric oxide values, either in stable lung transplant patients or in lung transplant patients with chronic rejection.

Adolescent↗
PubMed1995

The safety of air transportation of patients with advanced lung disease. Experience with 21 patients requiring lung transplantation or pulmonary thromboendarterectomy.

Air travel can cause severe respiratory decompensation in a patient with advanced lung disease due to high altitude hypoxemia. We report our experience in flying 21 patients with advanced lung disease to a medical center remote from Israel for lung transplantation or pulmonary thromboendarterectomy (PTE). All patients had severe lung disease with marked hypoxemia (PaO2, 40 to 59) and 16 had significant pulmonary hypertension. Nine patients (with emphysema and pulmonary fibrosis) required single lung transplant, four (with cystic fibrosis and emphysema) required double-lung transplant, six (with primary or secondary pulmonary hypertension) required heart-lung transplant, and two (with major vessel pulmonary thrombosis) required PTE. All patients were flown by commercial aircraft to centers located 2,634 to 13,181 km away from Israel. Length of flight was between 4 and 21 h. Patients were given oxygen supplementation during the flight and were monitored by portable oximeters. All but three patients were hemodynamically stable and 19 of them were escorted by physicians. All but one hemodynamically unstable patient who died on board arrived safely at their destinations. We conclude that with careful preparation, sufficient oxygen supply, oximetric monitoring, and medical escort, almost any patient with severe lung disease can travel by air to any necessary destination.

Adult↗
PubMed2005

Positron emission tomography demonstrates radiation-induced changes to nonirradiated lungs in lung cancer patients treated with radiation and chemotherapy.

STUDY OBJECTIVES: To determine whether acute changes in shielded lungs can be detected by positron emission tomography (PET) after radiation therapy. DESIGN: Retrospective cohort study. SETTING: University-affiliated medical center. PATIENTS: Sixteen patients undergoing radiation therapy for lung cancer who had PET scans after receiving treatment. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Thirteen of 16 patients (81.2%) showed increased (18)fluoro-2-deoxyglucose uptake in shielded nonirradiated lung in the following four distinct patterns: (1) contralateral peripheral pleural uptake in 5 of 16 patients (31.2%); (2) ipsilateral peripheral pleural uptake in 5 of 16 patients (31.2%); (3) bilateral peripheral pleural uptake in 1 of 16 patients (6.2%); and (4) bilateral diffuse background uptake in 1 of 16 patients (6.2%). This last patient developed clinically evident radiation pneumonitis. CONCLUSIONS: Increased lung metabolic activity can be demonstrated in the nonirradiated lung in patients who have undergone radiation therapy for lung cancer and can be detected by PET scanning. PET scanning of lungs in irradiated patients may provide an early demonstrable barometer of pulmonary toxicity. If verified, this imaging tool could prove to be useful in monitoring patients receiving radiation therapy for thoracic malignancies and may have predictive value for subsequent fibrosis. PET scanning may also be an important tool in future studies to further elucidate the pathogenetic mechanism of radiation-induced lung injury.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Single lung transplantation for severe chronic obstructive pulmonary disease. Washington University Lung Transplant Group.

Single lung transplantation (SLT) has been considered physiologically inappropriate for patients with chronic obstructive pulmonary disease (COPD). It has been postulated that the high static compliance and elevated pulmonary vascular resistance of the native lung functioning in parallel with the more normal allografted lung could cause unacceptable ventilation-perfusion mismatching and/or overinflation of the native lung with encroachment on the expansion of the transplanted lung. While some degree of ventilation-perfusion imbalance may be physiologically obligatory after SLT for COPD, a significant disruption in gas exchange may not occur unless a complication, such as rejection or infection, arises in the transplanted lung. A 60-year-old man with COPD who underwent successful SLT is presented and discussed. In spite of scintigraphic evidence of ventilation-perfusion mismatching between the native lung and the allograft during the first six postoperative weeks, the recipient had normal resting gas exchange on room air after the second postoperative week. Fourteen weeks after transplantation, his maximum oxygen uptake was 37.3 percent of the predicted maximal value, and no evidence of ventilatory limitation was detected. His functional status and lifestyle have been markedly improved by SLT. The role of SLT for COPD should be reconsidered. It may be a reasonable transplantation alternative for selected patients with COPD who are not candidates for double lung transplantation (DLT).

Exercise↗
PubMedDate not supplied

Dependent lung opacity at thin-section CT: evaluation by spirometrically-gated CT of the influence of lung volume.

OBJECTIVE: To evaluate the influence of lung volume on dependent lung opacity seen at thin-section CT. MATERIALS AND METHODS: In thirteen healthy volunteers, thin-section CT scans were performed at three levels (upper, mid, and lower portion of the lung) and at different lung volumes (10, 30, 50, and 100% vital capacity), using spirometric gated CT. Using a three-point scale, two radiologists determined whether dependent opacity was present, and estimated its degree. Regional lung attenuation at a level 2 cm above the diaphragm was determined using semiautomatic segmentation, and the diameter of a branch of the right lower posterior basal segmental artery was measured at each different vital capacity. RESULTS: At all three anatomic levels, dependent opacity occurred significantly more often at lower vital capacities (10, 30%) than at 100% vital capacity (p = 0.001). Visually estimated dependent opacity was significantly related to regional lung attenuation (p < 0.0001), which in dependent areas progressively increased as vital capacity decreased (p < 0.0001). The presence of dependent opacity and regional lung attenuation of a dependent area correlated significantly with increased diameter of a segmental arterial branch (r = 0.493 and p = 0.0002; r = 0.486 and p = 0.0003, respectively). CONCLUSION: Visual estimation and CT measurements of dependent opacity obtained by semiautomatic segmentation are significantly influenced by lung volume and are related to vascular diameter.

Adult↗
PubMed2006

ZD6474, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, inhibits growth of experimental lung metastasis and production of malignant pleural effusions in a non-small cell lung cancer model.

ZD6474 is a novel, orally active inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, with some additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. The purpose of this study was to determine the potential of ZD6474 in the control of established experimental lung metastasis and pleural effusions produced by human non-small cell lung cancer (NSCLC) cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells express high levels of EGFR and only PC14PE6 cells overexpress VEGF. Neither ZD6474 nor the EGFR tyrosine kinase inhibitor gefitinib inhibit proliferation of PC14PE6 or H226 cells in vitro. Both PC14PE6 and H226 cells inoculated intravenously into nude mice induced multiple lung nodules after 5-7 weeks. In addition, PC14PE6 cells produced bloody pleural effusions. Daily oral treatment with ZD6474 did not reduce the number of lung nodules produced by PC14PE6 or H226 cells, but did reduce the lung weight and the size of lung nodules. ZD6474 also inhibited the production of pleural effusions by PC14PE6 cells. Histological analyses of lung lesions revealed that ZD6474 treatment inhibited activation of VEGFR-2 and reduced tumor vascularization and tumor cell proliferation. Therapeutic effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib was inactive in this model. These results indicate that ZD6474, an inhibitor of VEGFR-2, may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC.

Angiogenesis Inhibitors↗
PubMed2003

Primary and secondary prevention of non-small-cell lung cancer: the SPORE Trials of Lung Cancer Prevention.

The aims of chemoprevention in lung cancer are to prevent the appearance of disease (primary prevention) and to stop or reverse the progression of premalignant lesions (secondary prevention). Until recently, there was little hope that these goals could be attained. However, the results achieved with tamoxifen in the prevention of breast cancer, and the emergence of new therapies specifically targeted to molecules involved in the pathogenesis of lung cancer have set the stage for investigation of these agents for chemoprevention of lung cancer. Two of these new molecular targeted agents are gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase activity, and tipifarnib (R115777, Zarnestra ), an inhibitor of the farnesyltransferase enzyme, which is required for the proper localization and function of the ras oncogene. Tumor responses and disease stabilization have been achieved with both agents in clinical trials. In the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 phase II trials, gefitinib was demonstrated to be effective for disease control in patients with advanced non-small-cell lung cancer. The SPORE (Specialized Program of Research Excellence) Trials of Lung Cancer Prevention (STOP) are 2 parallel studies that will investigate the potential effectiveness of gefitinib and tipifarnib in preventing the appearance and progression of premalignant lesions in former or current smokers with a history of smoking-related cancer. These trials should provide information not only about the potential role of gefitinib and tipifarnib in lung cancer chemoprevention, but also about the molecular changes that underlie tumorigenesis and that may serve as markers of disease progression. The STOP trial objectives are to evaluate the effect of gefitinib and tipifarnib on histologic and biologic parameters in patients with evidence of sputum atypia, to evaluate various parameters as potential predictors of the effectiveness of these agents, and to evaluate the tolerability of these agents over a 6-month course of treatment. Histologic response, defined as prevention of appearance or progression of premalignant lesions, is the primary endpoint of these trials. New targeted molecular therapies such as gefitinib and tipifarnib may offer the opportunity to make chemoprevention a viable treatment modality in lung cancer as well as in other human solid tumors.

Antineoplastic Agents↗
PubMed1999

[Estimation of pulmonary hypertension in lung and valvular heart diseases by perfusion lung scintigraphy].

To estimate pulmonary hypertension, we measured postural differences in pulmonary blood flow for the lateral decubitus positions on perfusion lung scintigrams with Tc-99 m macro-aggregated albumin, applying the method devised by Tanaka et al (Eur J Nucl Med 17: 320-326, 1990). Utilizing a scintillation camera coupled to a minicomputer system, changes in the distribution of pulmonary blood flow caused by gravitational effects, namely, changes in the total count ratios for the right lung versus the left lung in the right and left lateral decubitus positions (R/L), were obtained for 44 patients with lung disease, 95 patients with valvular heart disease, and 23 normal subjects. Mean standard deviation in the R/L ratios was 3.09 +/- 1.28 for the normal subjects, 1.97 +/- 0.89 for the patients with lung disease, and 1.59 +/- 0.59 for the patients with valvular heart disease. The R/L ratios correlated with mean pulmonary arterial pressure and cardio-thoracic ratios in the lung disease and valvular heart disease groups, with pulmonary arteriolar resistance in the former, and with pulmonary capillary wedge pressure in the latter. Defining pulmonary hypertension (> 20 mmHg) as an R/L ratio of less than 1.81, which is the mean-1 standard deviation for normal subjects, the sensitivity and the specificity of the R/L ratio for the diagnosis of pulmonary hypertension were 62.9% and 76.2%, respectively, for the lung disease patients, and 80.3% and 61.8%, respectively, for the valvular heart disease patients. This method seems to be useful for the pathophysiologic evaluation of pulmonary perfusion in cases of lung disease and valvular heart disease.

Adult↗
PubMed1999

Compensatory lung growth after partial pneumonectomy enhances lung tumorigenesis induced by 3-methylcholanthrene.

In small mammals, partial pneumonectomy (PNX) elicits rapid hyperplastic compensatory growth of the remaining lung parenchyma to restore normal lung mass, structure, and function. In BALB mice subjected to PNX, compensatory lung growth is complete within 10 days. Because cellular hyperplasia contributes to the mechanism of tumor promotion by butylated hydroxytoluene (BHT), we hypothesized that hyperplastic compensatory lung growth would promote tumor formation in carcinogen-treated animals in a manner similar to that observed after BHT. In mice subjected to PNX, within 1 week of treatment with the carcinogen 3-methylcholanthrene (MCA; 10 microg/g body weight), lung tumor multiplicity was 3-7-fold higher in animals subjected to PNX than in mice subjected to a sham operation. The increase in tumor multiplicity occurred when PNX was performed 1, 3, and 6 days before or 1 day after MCA treatment. In the absence of PNX, lung tumor multiplicity in MCA-treated mice given one injection of BHT (200 mg/kg body weight) increased significantly (P < 0.01) as compared to that in mice given MCA alone. Tumor multiplicity continued to increase linearly (R2 = 0.99) with each subsequent BHT injection. Lung tumor multiplicity and tumor size in mice given one or two injections of BHT were comparable to those in animals subjected to PNX. These data demonstrate that post-PNX compensatory lung growth stimulates tumorigenesis in MCA-treated mice and provides a novel model for investigating tumor formation.

Animals↗
PubMed2000

ONYX-015 works synergistically with chemotherapy in lung cancer cell lines and primary cultures freshly made from lung cancer patients.

p53 mutations and loss of heterozygosity (LOH) have been detected in >50% of lung cancers. Wild-type p53 can prevent replication of damaged DNA and promote apoptosis of cells with abnormal DNA. A human adenovirus, ONYX-015, which has a deletion in the E1B region, has shown tumor-specific cytolytic effect in tumor cells with nonfunctional p53 and antitumor efficacy that can be augmented by chemotherapeutic agents. A recent report from an independent group, however, indicates that wild-type p53 is necessary for the infection of this replicating virus, and it is in direct contradiction to previous observations of the ONYX group. In this study, we carried out cytopathic effect (CPE) assays using ONYX-015 on five human lung cancer cell lines with known p53 status. Two of these cell lines, NCI-H522 and NCI-H1703, have mutations and LOH in their p53 gene. Both lines were lysed in a dose-dependent manner and showed 100% cytolysis at a multiplicity of infection of 0.1. Two additional cell lines, NCI-H2347 and NCI-H838, both of which have wild-type p53 gene, showed near complete lysis at a multiplicity of infection of 1. We demonstrate here that the lung cancer cells with nonfunctional p53 are at least 10 times more sensitive to ONYX-015 cytolysis than the lung cancer cells with wild-type p53. In addition, standard chemotherapeutic agents (paclitaxol and cisplatin) showed a synergistic effect when combined with ONYX-015, and this effect was p53 mutant dependent. Furthermore, we tested the cytolytic effect of ONYX-015 on a panel (n = 7) of primary first-passage cultures made from freshly resected lung cancers. ONYX-015 lysed primary lung cancer cells in six of seven (86 %) primary cultures. Two of four primary cultures treated with chemotherapeutic agents had a synergistic effect with ONYX-015. Our data indicate that wild-type p53 is not required for the infection of this replicating virus, and also we demonstrate that ONYX-015 is effective alone and works synergistically with chemotherapeutic agents in lung cancer cell lines and primary cultures. This study suggests that ONYX-015 may be effective, especially in combination with conventional chemotherapy, in the treatment of patients with lung cancer.

Adenoviridae↗